Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency.

Autor:	Riedhammer KM; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.; Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany., Burgemeister AL; Genetikum, Genetic Counseling and Diagnostics, 70173 Stuttgart, Germany., Cantagrel V; Developmental Brain Disorders Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR, 75015 Paris, France., Amiel J; Department of Genetics, AP-HP, Necker Enfants Malades Hospital, Université Paris Cité, Imagine Institute, 75015 Paris, France., Siquier-Pernet K; Developmental Brain Disorders Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR, 75015 Paris, France., Boddaert N; Département de radiologie pédiatrique, INSERM UMR 1163 and INSERM U1000, AP-HP, Necker Enfants Malades Hospital, 75015 Paris, France., Hertecant J; Division of Genetics and Metabolics, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates., Kannouche PL; CNRS UMR 9019, Université Paris-Saclay, Equipe labellisée Ligue contre le Cancer, Gustave Roussy, 94805 Villejuif, France., Pouvelle C; CNRS UMR 9019, Université Paris-Saclay, Equipe labellisée Ligue contre le Cancer, Gustave Roussy, 94805 Villejuif, France., Htun S; Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA 94143, USA., Slavotinek AM; Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA 94143, USA., Beetz C; Centogene GmbH, 18055 Rostock, Germany., Diego-Alvarez D; Centogene GmbH, 18055 Rostock, Germany., Kampe K; Centogene GmbH, 18055 Rostock, Germany., Fleischer N; FDNA Inc., Boston, MA 02111, USA., Awamleh Z; Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada., Weksberg R; Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.; Department of Molecular Genetics, Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A1, Canada., Kopajtich R; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany., Meitinger T; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany., Suleiman J; Division of Neurology, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates.; Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates., El-Hattab AW; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.; Pediatrics Department, University Hospital Sharjah, Sharjah, United Arab Emirates.; Genetics and Metabolic Department, KidsHeart Medical Center, Abu Dhabi, United Arab Emirates.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2022 Sep 10; Vol. 31 (18), pp. 3083-3094.
DOI:	10.1093/hmg/ddac098
Abstrakt:	Background: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. Methods: Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. Results: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1 and HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. Conclusion: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome. (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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